US3953501A - Triiodoisophthalic acid monoamino acid amides - Google Patents
Triiodoisophthalic acid monoamino acid amides Download PDFInfo
- Publication number
- US3953501A US3953501A US05/331,110 US33111073A US3953501A US 3953501 A US3953501 A US 3953501A US 33111073 A US33111073 A US 33111073A US 3953501 A US3953501 A US 3953501A
- Authority
- US
- United States
- Prior art keywords
- triiodobenzoyl
- carboxy
- methylamide
- acid
- acetamido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001408 amides Chemical class 0.000 title claims description 9
- QMADWSQEVHUFFJ-UHFFFAOYSA-N 2,4,5-triiodobenzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(I)=C(I)C(C(O)=O)=C1I QMADWSQEVHUFFJ-UHFFFAOYSA-N 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 239000002253 acid Substances 0.000 claims abstract description 29
- -1 heterocyclic amino acid Chemical class 0.000 claims description 33
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 229940024606 amino acid Drugs 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 16
- 150000001413 amino acids Chemical class 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 125000001589 carboacyl group Chemical group 0.000 claims description 5
- QBSXGLVPMKEGPH-UHFFFAOYSA-N 3-acetamido-2,4,6-triiodo-5-[[1-(methylamino)-1-oxopropan-2-yl]carbamoyl]benzoic acid Chemical compound CNC(=O)C(C)NC(=O)C1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I QBSXGLVPMKEGPH-UHFFFAOYSA-N 0.000 claims description 3
- YYUHACJBBYFXIH-UHFFFAOYSA-N 3-acetamido-5-(carboxymethylcarbamoyl)-2,4,6-triiodobenzoic acid Chemical compound CC(=O)NC1=C(I)C(C(O)=O)=C(I)C(C(=O)NCC(O)=O)=C1I YYUHACJBBYFXIH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- OWUZLJFGHWBXBC-UHFFFAOYSA-N 2,4,6-triiodo-3-[(2-methoxyacetyl)amino]-5-[[1-(methylamino)-1-oxobutan-2-yl]carbamoyl]benzoic acid Chemical compound CNC(C(CC)NC(C1=C(C(=C(C(=C1I)NC(COC)=O)I)C(=O)O)I)=O)=O OWUZLJFGHWBXBC-UHFFFAOYSA-N 0.000 claims description 2
- DCRDQUMROYERPS-UHFFFAOYSA-N 2,4,6-triiodo-3-[(2-methoxyacetyl)amino]-5-[[1-(methylamino)-1-oxopropan-2-yl]carbamoyl]benzoic acid Chemical compound CNC(=O)C(C)NC(=O)C1=C(I)C(NC(=O)COC)=C(I)C(C(O)=O)=C1I DCRDQUMROYERPS-UHFFFAOYSA-N 0.000 claims description 2
- XHAVPBLEDGMJTF-UHFFFAOYSA-N 2,4,6-triiodo-3-[(2-methoxyacetyl)amino]-5-[[3-methyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]benzoic acid Chemical compound CNC(=O)C(C(C)C)NC(=O)C1=C(I)C(NC(=O)COC)=C(I)C(C(O)=O)=C1I XHAVPBLEDGMJTF-UHFFFAOYSA-N 0.000 claims description 2
- MHPAVJWAUAOOTO-UHFFFAOYSA-N 2,4,6-triiodo-3-[(2-methoxyacetyl)amino]-5-[methyl-[2-(methylamino)-2-oxoethyl]carbamoyl]benzoic acid Chemical compound CNC(=O)CN(C)C(=O)C1=C(I)C(NC(=O)COC)=C(I)C(C(O)=O)=C1I MHPAVJWAUAOOTO-UHFFFAOYSA-N 0.000 claims description 2
- OIOFBRLYKRFJQU-UHFFFAOYSA-N 2,4,6-triiodo-3-[[2-(methylamino)-2-oxoethyl]carbamoyl]-5-(pentanoylamino)benzoic acid Chemical compound CCCCC(=O)NC1=C(I)C(C(O)=O)=C(I)C(C(=O)NCC(=O)NC)=C1I OIOFBRLYKRFJQU-UHFFFAOYSA-N 0.000 claims description 2
- NPCYYZYVQAQDBM-UHFFFAOYSA-N 3-[[3-hydroxy-1-(methylamino)-1-oxopropan-2-yl]carbamoyl]-2,4,6-triiodo-5-[(2-methoxyacetyl)amino]benzoic acid Chemical compound CNC(=O)C(CO)NC(=O)C1=C(I)C(NC(=O)COC)=C(I)C(C(O)=O)=C1I NPCYYZYVQAQDBM-UHFFFAOYSA-N 0.000 claims description 2
- DXTZJZKFDYRDPP-UHFFFAOYSA-N 3-acetamido-2,4,6-triiodo-5-[[1-(methylamino)-1-oxobutan-2-yl]carbamoyl]benzoic acid Chemical compound CNC(C(CC)NC(C1=C(C(=C(C(=C1I)NC(C)=O)I)C(=O)O)I)=O)=O DXTZJZKFDYRDPP-UHFFFAOYSA-N 0.000 claims description 2
- WJFQXRIZTZYQFX-UHFFFAOYSA-N 3-acetamido-2,4,6-triiodo-5-[[3-(methylamino)-3-oxopropyl]-phenylcarbamoyl]benzoic acid Chemical compound C=1C=CC=CC=1N(CCC(=O)NC)C(=O)C1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I WJFQXRIZTZYQFX-UHFFFAOYSA-N 0.000 claims description 2
- QTIBOZWDIULMGJ-UHFFFAOYSA-N 3-acetamido-2,4,6-triiodo-5-[[3-(methylamino)-3-oxopropyl]carbamoyl]benzoic acid Chemical compound CNC(=O)CCNC(=O)C1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I QTIBOZWDIULMGJ-UHFFFAOYSA-N 0.000 claims description 2
- DMASZHVDNIQSGG-UHFFFAOYSA-N 3-acetamido-2,4,6-triiodo-5-[[3-methyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]benzoic acid Chemical compound CNC(=O)C(C(C)C)NC(=O)C1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I DMASZHVDNIQSGG-UHFFFAOYSA-N 0.000 claims description 2
- HCFQXMPCMVTNKF-UHFFFAOYSA-N 3-acetamido-2,4,6-triiodo-5-[methyl-[2-(methylamino)-2-oxoethyl]carbamoyl]benzoic acid Chemical compound CNC(=O)CN(C)C(=O)C1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I HCFQXMPCMVTNKF-UHFFFAOYSA-N 0.000 claims description 2
- XDALJUNEVNKUBG-UHFFFAOYSA-N 3-acetamido-5-[(2-aminoacetyl)carbamoyl]-2,4,6-triiodobenzoic acid Chemical compound CC(=O)NC1=C(I)C(C(O)=O)=C(I)C(C(=O)NC(=O)CN)=C1I XDALJUNEVNKUBG-UHFFFAOYSA-N 0.000 claims description 2
- YNNPKFBRNNPSLD-UHFFFAOYSA-N 3-acetamido-5-[[2-(dimethylamino)-2-oxoethyl]carbamoyl]-2,4,6-triiodobenzoic acid Chemical compound CN(C)C(=O)CNC(=O)C1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I YNNPKFBRNNPSLD-UHFFFAOYSA-N 0.000 claims description 2
- CMPHZDSEQHQMQN-UHFFFAOYSA-N 3-acetamido-5-[[3-hydroxy-1-(methylamino)-1-oxopropan-2-yl]carbamoyl]-2,4,6-triiodobenzoic acid Chemical compound CNC(=O)C(CO)NC(=O)C1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I CMPHZDSEQHQMQN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 102000012210 Proprotein Convertase 5 Human genes 0.000 claims 1
- 108010022052 Proprotein Convertase 5 Proteins 0.000 claims 1
- HHFIATHHSBFCBY-UHFFFAOYSA-N ioglicic acid Chemical compound CNC(=O)CNC(=O)C1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I HHFIATHHSBFCBY-UHFFFAOYSA-N 0.000 claims 1
- 150000007513 acids Chemical class 0.000 abstract description 9
- 239000003795 chemical substances by application Substances 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 7
- 150000003862 amino acid derivatives Chemical class 0.000 abstract description 5
- 239000002872 contrast media Substances 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 4
- 229940039231 contrast media Drugs 0.000 abstract description 3
- 238000000354 decomposition reaction Methods 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- 238000004458 analytical method Methods 0.000 description 41
- 239000000243 solution Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 26
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 22
- 239000012346 acetyl chloride Substances 0.000 description 22
- 239000000047 product Substances 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000013019 agitation Methods 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
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- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000004471 Glycine Substances 0.000 description 7
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 7
- 239000012266 salt solution Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000009608 myelography Methods 0.000 description 6
- JJKWHOSQTYYFAE-UHFFFAOYSA-N 2-methoxyacetyl chloride Chemical compound COCC(Cl)=O JJKWHOSQTYYFAE-UHFFFAOYSA-N 0.000 description 5
- LQDUOEUIYVUSDD-UHFFFAOYSA-N 3-amino-2,4,6-triiodo-5-[[2-(methylamino)-2-oxoethyl]carbamoyl]benzoic acid Chemical compound CNC(=O)CNC(=O)C1=C(I)C(N)=C(I)C(C(O)=O)=C1I LQDUOEUIYVUSDD-UHFFFAOYSA-N 0.000 description 5
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- 229910021529 ammonia Inorganic materials 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 description 5
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- DQTOZIJNMYYCJE-UHFFFAOYSA-N methyl 3-carbonochloridoyl-5-nitrobenzoate Chemical compound COC(=O)C1=CC(C(Cl)=O)=CC([N+]([O-])=O)=C1 DQTOZIJNMYYCJE-UHFFFAOYSA-N 0.000 description 4
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- FLYHBFOGYIBAFQ-UHFFFAOYSA-N 2-[(3-methoxycarbonyl-5-nitrobenzoyl)amino]acetic acid Chemical compound COC(=O)C1=CC(C(=O)NCC(O)=O)=CC([N+]([O-])=O)=C1 FLYHBFOGYIBAFQ-UHFFFAOYSA-N 0.000 description 3
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
Definitions
- This invention relates to triiodoisophthalic acid monoamino acid amides (amino acid derivatives of the acylamino-5-alkylcarbamoyl-2,4,6-triiodobenzoic acids), processes for the preparation thereof, and the use thereof as radiopaque agents, especially as X-ray contrast media for illustrating the urinary tract system, the cardiovascular system and the body cavities containing cerebro-spinal fluid.
- 3-ACYLAMINO-5-ALKYLCARBAMOYL-2,4,6-TRIIODOBENZOIC ACIDS ARE KNOWN FROM U.S. Pat. No. 3,145,197.
- 3-acylamino-5-alkylcarbamoyl-2,4,6-triiodobenzoic acids have likewise been described, e.g., 5-acetamido-2,4,6-triiodoisophthaloyl digylcine in U.S. Pat. No.
- Another object of this invention is to provide novel intermediates useful in the production of triiodoisophthalic acid monoamino acid amides.
- a further object of this invention is to provide useful radiopaque compositions and methods for their use.
- ##EQU1## is divalent amino lower alkanoyl derived from a naturally occuring amino acid
- R is lower alkyl, hydroxyalkyl or alkoxyalkyl
- X and Y are different from each other and each represent hydroxy or ##EQU2## wherein R 1 and R 2 are each hydrogen, lower alkyl or hydroxyalkyl, or R 1 and R 2 together with the nitrogen atom form a 5 to 7 member heterocyclic ring which can contain a further oxygen, nitrogen or sulfur hetero atom; and the physiologically acceptable salts thereof.
- compounds of Formula E are prepared by N-acylating a novel compound of the Formula Z: ##SPC2##
- X and Y have the above-indicated values, with an amino acylating agent of the formula R--CO--W wherein R has the above-indicated values and W is a carboxylic acid functional group.
- amino acid derivatives of this invention possess a high physiological compatibility and are highly suitable not only for uro- and angiography, but also for myelography.
- the divalent aminoloweralkanoyl radical ##EQU4## is derived from an aminocarboxylic acid, which can assume any desired configuration. One or two amino groups can be disposed in any desired position, although the ⁇ -aminocarboxylic acids are preferred. Furthermore, the aminocarboxylic acids can also be unsaturated, branched, polybasic, and substituted in the usual manner, for example, by hydroxy groups, mercapto groups, optionally substituted aryl, cycloalkyl or heterocyclic groups. Also, the amino group can be substituted by aliphatic, aromatic or mixed aromatic-aliphatic groups.
- Suitable aminocarboxylic acids include but are not limited to glycine, sarcosine, alanine, N-phenylalanine, N-benzylalanine, valine, leucine, isoleucine, serine, threonine, aminobutyric acid, cysteine, methionine, ornithine, lysine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, phenylalanine, tyrosine, proline, hydroxyproline, tryptophan and histidine as well as ⁇ -amino acids, e.g., ⁇ -alanine, or oligopeptides, e.g., glycyl glycine, glycyl L-leucine, etc. Of these, preferred are glycine, sarcosine, alanine, valine, leucine, serine, threonine and proline.
- the alkyl, hydroxyalkyl, alkoxy and alkanoyl residues when present are preferably lower residues, e.g., lower alkyl of 1-6 carbon atoms, preferably 1-4 carbon atoms such as methyl, ethyl, propyl, isopropyl or butyl; hydroxyalkyl of 1-6 carbon atoms, preferably 1-4 carbon atoms, e.g., hydroxymethyl, hydroxyethyl or hydroxypropyl; lower alkoxy of 1-4 carbon atoms, preferably 1-2 carbon atoms such as methoxy or ethoxy; lower alkanoyl of 1-6 carbon atoms, and especially lower alkanoyl of 1-4 carbon atoms such as acetyl, propionyl, butyryl and isobutyryl.
- lower alkyl of 1-6 carbon atoms preferably 1-4 carbon atoms such as methyl, ethyl, propyl, isopropyl or buty
- R 1 and R 2 together with the nitrogen atom form a heterocyclic ring preferred are those of pyrrolidine, morpholine or piperazine.
- the compounds of this invention according to Formula E include both the free compounds and their metal, ammonium and amine salts, preferably the water-soluble and non-toxic physiologically acceptable salts, although water-insoluble and/or toxic salts can readily be used for isolation and/or characterization purposes. These compounds, individually, or in admixture, are valuable radiopaque agents.
- Suitable salts of physiologically compatible bases include but are not limited to the alkali metal salts, e.g., sodium and potassium; the alkaline earth metal salts, e.g., calcium and magnesium; amine salts, e.g., ammonium, heterocyclic amines, e.g., morpholine and N-alkyl amines, hydroxyalkylamines, alkyl(hydroxyalkyl) amines and di(hydroxyalkyl)amines, wherein alkyl in each instance preferably contains 1-6, more preferably 1-4 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, including trimethylamine, diethylamine, ethanolamine, diethanolamine and polyhydroxyalkylamines, e.g., trihydroxy-tert.-butylamine, saccharidyl amines, including
- Preferred mono- and dialkyl glucamines are those compounds which contain, in one or both alkyl groups respectively, a total of one to four carbon atoms.
- Especially preferred alkylglucamine salts are the N-methyl and N,N-dimethyl salts.
- the salts can be employed alone or in admixture, e.g., an alkali metal salt can be partially replaced by a corresponding alkaline earth metal salt.
- Equivalents of the compounds of this invention are compounds otherwise corresponding structurally thereto and possessing the same activity where instead of a loweralkanoyl group there is present the acyl group of another organic acid, e.g., a carboxylic-acid containing up to 15 carbon atoms, especially intermediate (7-12) aliphatic carboxylic, preferably an alkanoic acid, which can be unsaturated, branched, polybasic, or substituted in the usual manner, e.g., by hydroxy or halogen atoms; a cycloaliphatic, aromatic and mixed aromatic-aliphatic (alkaryl and aralkyl) acid, which can likewise be substituted in the usual manner, examples of such equivalents being caproic acid, enanthic acid, undecyclic acid, oleic acid, trimethylacetic acid, dichloroacetic acid, cyclopentylpropionic acid, phenylpropionic acid, phenylacetic acid, phenoxyacetic acid, succ
- the acyl group of such equivalent compounds can also be that of sulfonic acid, e.g., an arylsulfonic, including benzenesulfonic, p-toluene-sulfonic, m,m'-dimethylbenzenesulfonic, o,o'-dimethylbenzenesulfonic, sym.-trimethylbenzenesulfonic, sym.-triethylbenzenesulfonic, m-ethylbenzenesulfonic, para-isopropylbenzenesulfonic, m-n-butylbenzenesulfonic acid, or an alkylsulfonic, e.g., methanesulfonic, ethanesulfonic, propanesulfonic, isopropanesulfonic, butanesulfonic, tert.-butanesulfonic, pentanesulfonic, isopent
- the novel compounds of this invention are valuable as X-ray contrast media.
- Concentrated aqueous solutions of salts of these acids with inorganic or organic bases possess a low toxicity, a high excretory capability, predominantly via the urinary tract system and are of excellent compatibility intracerebrally and cerebrally. With respect to the cisternal compatibility, the novel compounds are superior to the conventional radiopaque agents.
- Aqueous solutions of the physiologically acceptable water-soluble salts can be used an injection preparations for uro-, angio- and myelography.
- Preferred compounds of this invention are those compounds of Formula E which meet one or more of the following criteria:
- ##EQU5## is divalent aminoloweralkanoyl derived from a naturally occurring amino acid, preferably a monoaminomonocarboxylic acid or a heterocyclic amino acid, e.g., histidine, tryptophan, proline, etc.;
- R 1 and R 2 are hydrogen, alkyl of 1-6 carbon atoms or hydroxyalkyl of 2-6 carbon atoms, especially when the other of R 1 ahd R 2 is hydrogen,
- Table 1 lists the significant properties of illustrative compounds of this invention, denoted by A, B, C, D, E, F, G, in comparison with those of the structurally comparable, conventional substance H.
- D n-(3-methylaminocarbonyl-5-acetamido-2,4,6-triiodobenzoyl)-sarcosine.
- E N-(3-aminocarbonyl-5-acetamido-2,4,6-triiodbenzoyl)-glycine.
- G n-(3-carboxy-5-hydroxyacetamido-2,4,6-triiodobenzoyl)-glycine methylamide.
- test compounds were injected in varying doses (0.008 - 0.200 ml./kg.) by means of a Hamilton No. 710 syringe directly into the suboccipital cisterna of rats which were under a slight ether narcosis.
- Cerebral compatibility was likewise determined on rats.
- a catheter was affixed in the left common carotid artery; the distal end of the catheter, after having been passed through the lateral connective tissue of the neck, was fixed in the center of the back.
- the test compounds were cranially injected in varying doses (14.0 - 26.0 ml./kg.) into the artery.
- the ED 50 was determined in each case, i.e., the dose at which an undesired array of neurological symptoms (including convulsions and death) is evoked in 50% of the animals.
- the compounds of general Formula E of the present invention can be produced by reacting novel compounds of general Formula Z ##SPC3##
- X and Y have the aboveindicated values, with an amino acylating agent of the formula RCO--W, wherein R have the above-indicated value and W represents a carboxylic acid functional group, e.g., a carboxylic acid halide, an acid anhydride, or a carboxylic acid ester.
- Acylation is effected in the presence of catalytic amounts of a mineral acid, e.g., sulfuric acid or perchloric acid.
- Suitable acylation solvents are well known in the art and include but are not limited to excess acid anhydride, acid, acid esters or mixtures thereof.
- Preferred acylating agents are the carboxylic acid halides, preferably in a polar aprotic solvent, e.g., dimethylacetamide.
- R, R 1 and R 2 have the above-indicated values with amino acids in the presence of organic or inorganic bases or with amino acid esters, and optionally subsequently saponifying the thus obtained esters.
- the reaction with amino acids or amino acid esters is preferably conducted in a cyclic ether solvent, e.g., dioxane or tetrahydrofuran.
- the compounds of general Formula Z which represent a particularly important group of starting compounds, can be prepared in accordance with conventional processes.
- amino acid amides are obtained in a conventional manner by the reduction of amino acid alkyl esters with ammonia or with the corresponding amines.
- the compounds of the general Formula Z wherein X is ##EQU10## and Y is hydroxy can be produced, for example, by reacting 3-methoxycarbonyl-5-nitrobenzoyl chloride (J. Med. Chem. 6:24, 1963) with an amino acid to the corresponding N(3-methoxycarbonyl-5-nitrobenzoyl)-amino acid (VI); thereafter amidating the methoxycarbonyl group to VII, with a correspondingly substituted amine or ammonia; hydrogenating the nitro group; and iodating the amino compound (VIII) to IX.
- N-(3-methoxycarbonyl-5-nitrobenzoyl)-amino acid amide (I) can also be obtained by reacting the corresponding amino acid (VI) with an amine, e.g., in accordance with the method used to prepare mixed anhydrides.
- novel triiodized isophthalic acid monoamino acid amides of Formula E are valuable contrast agents for radiopaque materials and novel intermediates for the production of radiological contrast substances.
- One ore more of the compounds of this invention can be employed in mixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application which do not deleteriously react with the active compounds.
- suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, etc.
- solutions preferably aqueous solutions.
- Ampoules are convenient unit dosages, or multivials containing multiple unit dosages can be used.
- the soluble salts of this invention are preferably used in aqueous solution whereby the concentration of the salts is preferably between about 15 % by volume and about 75 % by volume.
- the amount of active agent per unit dosage is about 5 to 50 g., preferably 7 to 35 g.
- the acids in the form of their water-soluble physiologically compatible salts, are extraordinarily good radiopaque agents for myelography, urography, and angiography.
- the salt solutions are characterized by a relatively low viscosity and can be administered by intravenous injection.
- the salt solutions are furthermore distinguished by a good circulatory compatibility and a low toxicity.
- the starting compounds can be prepared as follows:
- Process 1 Under ice cooling, 378.0 g. (4.5 moles) of sodium bicarbonate is added to 193.3 g. (1.55 moles) of glycine methylamide hydrochloride in 3.75 liters of water. Over a period of 3 hours, 365.4 g. of 3-methoxycarbonyl-5-nitrobenzoyl chloride in 1.3 l. of acetone is added dropwise to this reaction mixture. Thereafter, the mixture is stirred for 11/2 hours at room temperature; the product is vacuum-filtered, washed free of salt with water, and dried under vacuum at 70° C.
- Process 2 8.5 g. (0.03 mole) of N-(3-metoxycarbonyl-5-nitrobenzoyl-glycine (VIa) dissolved in 130 ml. of absolute tetrahydrofuran, is cooled to -15° C., after the addition of 4.2 ml. of triethylamine, and mixed under agitation with 3 ml. of the ethyl ester of chlorocarbonic acid. The reaction mixture is agitated for about 10 minutes at -10° to -5° C., and a solution of 2.8 ml. of methylamine in 20 ml. of absolute tetrahydrofuran, cooled to -15° C., is gradually added thereto dropwise under agitation.
- VIa N-(3-metoxycarbonyl-5-nitrobenzoyl-glycine
- a solution of the ammonium salt of N-(3-carboxy-5-aminobenzoyl)-glycine methylamide, produced by hydrogention of 1.6 moles of the corresponding nitro compound, is replenished with water to 140 liters and, under agitation, 3.6 l. of concentrated hydrochloric acid and 3.5 l. of 2N KICl 2 solution are added thereto. After three days of agitation, the reaction product is filtered from the precipitate, thoroughly washed with water, then agitated for 2 hours with water, vacuum-filtered, and dried under vacuum at 70° C.
- the reaction mixture is extracted twice with ether, the acqueous phase is acidified with concentrated hydrochloric acid, the thus-precipitated oil is extracted repeatedly with ethyl acetate, and the combined ethyl acetate extracts, after washing with water and drying with sodium sulfate, are mixed with a stoichiometric amount of dicyclohexylamine. After allowing the reaction mixture to stand for some time, it is filtered off from the precipitated dicyclohexylammonium salt (m.p. 204°-205° C.
- N-(3-METHYLAMINOCARBONYL-5-AMINOTRIIDOBENZOYL)-GLYCINE (IXa) 43.7 g. (0.14 mole) of N-(3-methylaminocarbonyl-5-nitrobenzoyl)-glycine methylammonium salt (VIIa) in 0.6 l. of water is hydrogenated, with Raney nickel as the catalyst, at about 140 atm. gauge and at room temperature. After removel of the catalyst, 15.4 l. of water, 280 ml. of concentrated hydrochloric acid, and 280 ml. of 2N KICl 2 solution are added to the filtrate, and the mixture is stirred for 48 hours at room temperature.
- the product is allowed to stand for some time, the compound is vacuum-filtered, washed thoroughly with water, and then dissolved in 2.5 l. of water with the addition of the stoichiometric amount of 2N ammonia.
- the solution is treated for 2 hours with activated carbon and finally, after removal of the carbon, the filtrate is acidified with concentrated hydrochloric acid.
- the product is vacuum-filtered, washed with water, then stirred with water for a certain period of time, again filtered, and dried under vacuum at 70° C.
- the above-mentioned compound can also be obtained in a conventional manner by acetylation with acetic anhydride in glacial acetic acid in the pressure of concentrated sulfuric acid as the catalyst, with a yield of 52%, m.p. 282-283° C. (under decomposition).
- Example 1 36.5 g. (64%) of the desired compound, m.p. 245°-247° C. (under decomposition), is produced from 53.5 g. (0.080 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-L-proline methylamide (IV h) in 96 ml. of dimethylacetamide with 13.6 ml. of acetyl chloride.
- Example 2 Analogously to Example 1, the desired compound is produced from the corresponding 5-amino compound (IV k), m.p. 228°-230° C. (decomposition).
- the solution is agitated overnight.
- the mixture is concentrated under vacuum, the residue is stirred with 700 ml. of water, the precipitate is vacuum-filtered, carefully washed with water, and, while still moist, reprecipitated from dilute ammonia with concentrated hydrochloric acid.
- the acid is vacuum-filtered, washed well with water, stirred with fresh water, and, after another filtering step, dried under vacuum at 70° C.
- valeroyl chloride Under agitation and water cooling, 31.5 ml. of valeroyl chloride is added dropwise to 45.8 g. (0.073 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzyl)-glycine methylamide (Iv a), m.p. 252°-253° C. (under decomposition), in 120 ml. of dimethylacetamide.
- the product After agitating the reaction mixture overnight at room temprature, the product is precipitated by adding water; then, the product is vacuum-filtered and purified by dissolving the corresponding sodium salt and separation of the free acid by the addition of a mineral acid.
- the precipitate is vacuum-filtered, washed with water, the compound is dissolved with 2N NH 4 OH to form a neutral solution, treated with activated carbon, and, after the removal of the carbon, acidified with concentrated hydrochloric acid. After allowing the reaction mixture to stand for about 20 hours at room temperature, it is filtered, washed free of salt with water, and dried under vacuum at 70° C.
- N-(3-methylaminocarbonyl-5-propionylamido-2,4,6-triiodobenzoyl)-glycine is prepared with propionyl chloride.
- This product has a melting point of 284°-286° C. (under decomposition).
- the methyl ester obtained according to (a) is refluxed for 2 hours in alcohol, adding an excess of 1N sodium hydroxide solution; the product is precipitated with concentrated hydrochloric acid.
- the substance is identical to the compound according to Example 14, as determined by thin-layer chromatography and IR spectrum.
- the compound is obtained analogously to Example 1 by acetylation of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine morpholide (IV l), m.p. about 200° C. (under decomposition), in dimethylacetamide.
- This compound is prepared analogously to Example 1 from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine ethanolamide (IV m), m.p. 201°-202° C. (under decomposition). After concentrating the dimethylacetamide solution under vacuum, the residue is stored with saturated soda solution for 48 hours at room temperature, the acid is precipitated with concentrated hydrochloric acid, and once again purified by reprecipitation from aqueous ammonia with a mineral acid.
- the compound is obtained in accordance with Example 14 from N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-sarcosine (IX g), m.p. 228°-229° C. (under decomposition), and acetyl chloride in dimethylacetamide; this product has a melting point of 287°-289° C. (under decomposition).
- This compound is produced analogously to Example 14 from 61.5 g. (0.1 mole) of N-(3-aminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-glycine (IX b), m.p. 271°-272° C. (under decomposition ), in 120 ml. of dimethylacetamide and 22 ml. of acetyl chloride.
- Example 11 the above compound is obtained from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-serine methylamide (IV b), m.p. 259°-260° C. (under decomposition) and methoxyacetic acid/thionyl chloride in dimethylacetamide.
- This compound is produced analogously to Example 2 from N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-DL-threonine (IX f), m.p. 263°-264° C. (under decomposition) and acetyl chloride in dimethylacetamide.
- This compound, m.p. 277°-279°C. (under decomposition) is produced analogously to Example 2 from the corresponding triiodoamino compound (IX d), m.p. 239°-241° C. (under decomposition), and acetyl chloride in dimethylacetamide.
- This compound is produced analogously to Example 2 by acetylation of the 5-amino compound (IX e), m.p. 247°-248° C. (under decomposition), with acetyl chloride in dimethylacetamide.
- this compound is produced from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl-DL- ⁇ -aminobutyric acid methylamide (IV o), m.p. about 220° C. (under decomposition), and acetyl chloride.
- This compound is produced analogously to Example 11 by reacting N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL- ⁇ -aminobutyric acid methylamide (IV o), m.p. about 220° C. (under decomposition), with methoxyacetic acid/thionyl chloride.
- the above compound is produced in accordance with Example 11 from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-sarcosine methylamide (IV e), m.p. 238°-239° C. (under decomposition), and in methoxyacetyl chloride.
- Example 11 Analogously to Example 11, the above compound is prepared from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-valine methylamide (IV p), m.p. about 235° C (under decomposition), and methoxyacetyl chloride.
- Example 2 Analogously to Example 1, the above compound is produced from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-N-phenyl- ⁇ -alanine methylamide (IV s), m.p. about 220° C. (under decomposition), and acetyl chloride.
- this compound is obtained from N-(3-aminocarbonyl-5-amino-2,4,6-triiodobenzoyl)- ⁇ -alanine (IX c), m.p. about 190° C. (under decomposition), and methoxyacetic acid/thionyl chloride.
- this compound is obtained from N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-glycine (IX a), m.p. 265°-266° C. (under decomposition), and methoxyacetyl chloride.
- this compound is produced from N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-glycine (IX a), m.p. 265°-266° C., and acetoxyacetyl chloride with subsequent saponification of the acetoxyacetyl residue.
- this compound is produced from N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-glycylglycine (IX h), m.p. 245°-246° C. (under decomposition), and acetyl chloride in dimethylacetamide.
- this compound is prepared from N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-DL-serine (IX e), m.p. 247°-248° C. (under decomposition), and methoxyacetic acid/thionyl chloride.
- the solution is filled into ampoules or “multivials” and sterilized at 120° C. This solution contains 380 mg. I/ml.
- the solution is filled into ampoules or multivials and sterilized at 120° C. This solution contains 380 mg. I/ml.
- the solution is filled into ampoules or multivials and sterilized at 120° C. This solution contains 380 mg. I/ml.
- This solution is filled into ampoules or multivials and sterilized at 120° C. This solution contains 280 mg. I/ml.
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Abstract
New amino acid derivative of acylamino-5-alkylcarbamoyl-2,4,6-triiodobenzoic acids are described together with processes for their preparation and use and novel intermediates useful in preparing these compounds. The compounds are valuable radiopaque agents useful as X-ray contrast media.
Description
This invention relates to triiodoisophthalic acid monoamino acid amides (amino acid derivatives of the acylamino-5-alkylcarbamoyl-2,4,6-triiodobenzoic acids), processes for the preparation thereof, and the use thereof as radiopaque agents, especially as X-ray contrast media for illustrating the urinary tract system, the cardiovascular system and the body cavities containing cerebro-spinal fluid.
3-ACYLAMINO-5-ALKYLCARBAMOYL-2,4,6-TRIIODOBENZOIC ACIDS ARE KNOWN FROM U.S. Pat. No. 3,145,197. Several amino acid derivatives of 3-acylamino-5-alkylcarbamoyl-2,4,6-triiodobenzoic acids have likewise been described, e.g., 5-acetamido-2,4,6-triiodoisophthaloyl digylcine in U.S. Pat. No. 3,102,880 and N-[3-N-(alkyl-acylamino)-5-alkylcarbamoyl-2,4,6-triiodobenzoyl]-amino acids in Helv. Chim. Acta 54 (8): 2551-2559 (1971). Although these compounds have a low toxicity, they have several undesirable side effects. For example, they do not meet the high requirements to be fulfilled by a medium for myelography, e.g., see Ugeskrift for laeger 134 (18): 936 (1972) and Advances in X-Ray Technology 115: 683-684 (1971). A primary requirement for radiopaque agents useful in myelography is the cisternal compatibility.
Accordingly, it is a general object of this invention to provide new amino acid derivatives of the acylamino-5-alkylcarbamoyl-2,4,6-triiodobenzoic acids and methods for their preparation and use.
Another object of this invention is to provide novel intermediates useful in the production of triiodoisophthalic acid monoamino acid amides.
A further object of this invention is to provide useful radiopaque compositions and methods for their use.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
Briefly, the above and other objects are attained in accordance with one aspect of this invention by providing a triiodoisophthalic acid monoamino acid amide of the Formula E ##SPC1##
wherein ##EQU1## is divalent amino lower alkanoyl derived from a naturally occuring amino acid,
R is lower alkyl, hydroxyalkyl or alkoxyalkyl,
X and Y are different from each other and each represent hydroxy or ##EQU2## wherein R1 and R2 are each hydrogen, lower alkyl or hydroxyalkyl, or R1 and R2 together with the nitrogen atom form a 5 to 7 member heterocyclic ring which can contain a further oxygen, nitrogen or sulfur hetero atom; and the physiologically acceptable salts thereof.
In another aspect of this invention, compounds of Formula E are prepared by N-acylating a novel compound of the Formula Z: ##SPC2##
wherein ##EQU3## X and Y have the above-indicated values, with an amino acylating agent of the formula R--CO--W wherein R has the above-indicated values and W is a carboxylic acid functional group.
It has now been found that the amino acid derivatives of this invention possess a high physiological compatibility and are highly suitable not only for uro- and angiography, but also for myelography.
The divalent aminoloweralkanoyl radical ##EQU4## is derived from an aminocarboxylic acid, which can assume any desired configuration. One or two amino groups can be disposed in any desired position, although the α-aminocarboxylic acids are preferred. Furthermore, the aminocarboxylic acids can also be unsaturated, branched, polybasic, and substituted in the usual manner, for example, by hydroxy groups, mercapto groups, optionally substituted aryl, cycloalkyl or heterocyclic groups. Also, the amino group can be substituted by aliphatic, aromatic or mixed aromatic-aliphatic groups.
Suitable aminocarboxylic acids include but are not limited to glycine, sarcosine, alanine, N-phenylalanine, N-benzylalanine, valine, leucine, isoleucine, serine, threonine, aminobutyric acid, cysteine, methionine, ornithine, lysine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, phenylalanine, tyrosine, proline, hydroxyproline, tryptophan and histidine as well as β-amino acids, e.g., β-alanine, or oligopeptides, e.g., glycyl glycine, glycyl L-leucine, etc. Of these, preferred are glycine, sarcosine, alanine, valine, leucine, serine, threonine and proline.
The alkyl, hydroxyalkyl, alkoxy and alkanoyl residues when present are preferably lower residues, e.g., lower alkyl of 1-6 carbon atoms, preferably 1-4 carbon atoms such as methyl, ethyl, propyl, isopropyl or butyl; hydroxyalkyl of 1-6 carbon atoms, preferably 1-4 carbon atoms, e.g., hydroxymethyl, hydroxyethyl or hydroxypropyl; lower alkoxy of 1-4 carbon atoms, preferably 1-2 carbon atoms such as methoxy or ethoxy; lower alkanoyl of 1-6 carbon atoms, and especially lower alkanoyl of 1-4 carbon atoms such as acetyl, propionyl, butyryl and isobutyryl.
When R1 and R2 together with the nitrogen atom form a heterocyclic ring, preferred are those of pyrrolidine, morpholine or piperazine.
The compounds of this invention according to Formula E include both the free compounds and their metal, ammonium and amine salts, preferably the water-soluble and non-toxic physiologically acceptable salts, although water-insoluble and/or toxic salts can readily be used for isolation and/or characterization purposes. These compounds, individually, or in admixture, are valuable radiopaque agents.
Suitable salts of physiologically compatible bases include but are not limited to the alkali metal salts, e.g., sodium and potassium; the alkaline earth metal salts, e.g., calcium and magnesium; amine salts, e.g., ammonium, heterocyclic amines, e.g., morpholine and N-alkyl amines, hydroxyalkylamines, alkyl(hydroxyalkyl) amines and di(hydroxyalkyl)amines, wherein alkyl in each instance preferably contains 1-6, more preferably 1-4 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, including trimethylamine, diethylamine, ethanolamine, diethanolamine and polyhydroxyalkylamines, e.g., trihydroxy-tert.-butylamine, saccharidyl amines, including glucamine, N-monoalkylglucamines and N,N-dialkylglucamines. Preferred mono- and dialkyl glucamines are those compounds which contain, in one or both alkyl groups respectively, a total of one to four carbon atoms. Especially preferred alkylglucamine salts are the N-methyl and N,N-dimethyl salts. The salts can be employed alone or in admixture, e.g., an alkali metal salt can be partially replaced by a corresponding alkaline earth metal salt.
Equivalents of the compounds of this invention are compounds otherwise corresponding structurally thereto and possessing the same activity where instead of a loweralkanoyl group there is present the acyl group of another organic acid, e.g., a carboxylic-acid containing up to 15 carbon atoms, especially intermediate (7-12) aliphatic carboxylic, preferably an alkanoic acid, which can be unsaturated, branched, polybasic, or substituted in the usual manner, e.g., by hydroxy or halogen atoms; a cycloaliphatic, aromatic and mixed aromatic-aliphatic (alkaryl and aralkyl) acid, which can likewise be substituted in the usual manner, examples of such equivalents being caproic acid, enanthic acid, undecyclic acid, oleic acid, trimethylacetic acid, dichloroacetic acid, cyclopentylpropionic acid, phenylpropionic acid, phenylacetic acid, phenoxyacetic acid, succinic acid, benzoic acid; other examples being α-ethylbutyric, valeric, isovaleric, α-ethylvaleric, 2-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, enanthic, octanoic, undecyclic and palmitic acid; cyclic acids, preferably a cycloaliphatic acid containing 5-18 carbon atoms, e.g., cyclopropylideneacetic, cyclobutylcarboxylic, cyclopentylcarboxylic, cyclopentylacetic, cyclohexyl carboxylic, cyclohexylacetic and β-cyclohexylpropionic acid; carbocyclic aryl or alkaryl acids containing 6-18 carbon atoms and 1 or 2 rings, e.g., benzoic, 2-, 3-, or 4-methylbenzoic, 2, 3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dimethylbenzoic, ethylbenzoic, 2,3,6-trimethylbenzoic, and 3-methyl-α-napthhoic acid; an aralkyl acid containing 7 to 18 carbon atoms, e.g., β-phenylpropionic; a polybasic acid containing 2-18 carbon atoms and 1 to 5 hydroxy groups, e.g., glycolic, lactic, citric, tartaric, d-maleic, d-glyceric and salicyclic acid; the corresponding acids containing one, two or more of simple substituents, e.g., halo, alkoxy, acyloxy, etc., in the molecule, e.g., chloroacetic, fluoroacetic, trichloroacetic, trifluoroacetic, 2,3,4-trimethoxybenzoic, phenoxyacetic, α-naphthoxyacetic acid, etc.
The acyl group of such equivalent compounds can also be that of sulfonic acid, e.g., an arylsulfonic, including benzenesulfonic, p-toluene-sulfonic, m,m'-dimethylbenzenesulfonic, o,o'-dimethylbenzenesulfonic, sym.-trimethylbenzenesulfonic, sym.-triethylbenzenesulfonic, m-ethylbenzenesulfonic, para-isopropylbenzenesulfonic, m-n-butylbenzenesulfonic acid, or an alkylsulfonic, e.g., methanesulfonic, ethanesulfonic, propanesulfonic, isopropanesulfonic, butanesulfonic, tert.-butanesulfonic, pentanesulfonic, isopentanesulfonic, hexanesulfonic, heptanesulfonic, octylsulfonic or heterocyclic sulfonic, e.g, α-pyridinesulfonic, α-pyranesulfonic, α-thiophensulfonic, α-furansulfonic, α-tetrahydrofuransulfonic, or other alkyl-, carbocyclic and heterocyclic aryl-, alkaryl- and aralkyl-sulfonic acid, preferably one containing 1-8 carbon atoms and 0-2, preferably 0-1 N, S or O heteroatoms, which are preferably ring carbon atoms in a heterocyclic ring.
The novel compounds of this invention are valuable as X-ray contrast media. Concentrated aqueous solutions of salts of these acids with inorganic or organic bases possess a low toxicity, a high excretory capability, predominantly via the urinary tract system and are of excellent compatibility intracerebrally and cerebrally. With respect to the cisternal compatibility, the novel compounds are superior to the conventional radiopaque agents. Aqueous solutions of the physiologically acceptable water-soluble salts can be used an injection preparations for uro-, angio- and myelography.
Preferred compounds of this invention are those compounds of Formula E which meet one or more of the following criteria:
a. Compounds in which ##EQU5## is divalent aminoloweralkanoyl derived from a naturally occurring amino acid, preferably a monoaminomonocarboxylic acid or a heterocyclic amino acid, e.g., histidine, tryptophan, proline, etc.;
b. Compounds in which ##EQU6## is an oligopeptide, preferably a dipeptide and especially when at least one of the peptide units is glycine, valine or leucine,
c. Compounds in which R is alkyl, hydroxyalkyl or alkoxyalkyl of 1-3 carbon atoms,
d. Compounds in which one of X and Y is hydroxy, especially those in which X is hydroxy,
e. Compounds in which one of R1 and R2 is hydrogen, alkyl of 1-6 carbon atoms or hydroxyalkyl of 2-6 carbon atoms, especially when the other of R1 ahd R2 is hydrogen,
f. Compounds in which one of X and Y is morpholino, pyrrolidino, or piperazino, especially when the other of X and Y is hydroxy
Specific compounds of Formula I, in addition to those shown in the Examples, include
N-3-carboxy-5-methoxyacetamido-2.4.6.-triiodobenzoyl)-DL-threonine Methylamide,
N-(3-carboxy-5-methoxyacetamido-2.4.6-triiodobenzoyl)-O-methyl-DL-serine Methylamide,
N-(3-methylaminocarbonyl-5-acetamido-2.4.6-triiodobenzoyl)-O-methyl-DL-serine,
N-(3-carboxy-5-methoxyacetamido-2.4.6-triiodobenzoyl)-N-methyl-β-alanine Methylamide,
N-(3-carboxy-5-acetamido-2.4.6-triiodobenzoyl)-N-methyl-DL-alanine Methylamide,
N-(3-methylaminocarbonyl-5-acetamido-2.4.6-triiodobenzyl)-N-cyclohexyl-.beta.-alanine,
N-(3-aminocarbonyl-5-acetamido-2.4.6-triiodobenzoyl)-N-methyl Alanine,
N-(3-methylaminocarbonyl-5-methoxyacetamido-2.4.6-triiodobenzoyl)-N-methyl-β-alanine,
N-(3-methylaminocarbonyl-5-acetamido-2.4.6-triiodobenzoyl)-DL-alanine,
N-(3-methylaminocarbonyl-5-hydroxyacetamido-2.4.6-triiodobenzoyl)-γ-aminobutyric Acid,
N-(3-carboxy-5-acetamido-2.4.6-triiodobenzoyl)-γ-aminobutyric acid Amide,
N-(3-methylaminocarbonyl-5-methoxyacetamido-2.4.6-triiodobenzoyl)-DL-phenyl-glycine,
N-(3-carboxy-5-acetamido-2.4.6-triiodobenzoyl)-L-glutamic Acid-bis [methylamide],
N-(3-methylaminocarbonyl-5-methoxyacetamido-2.4.6-triiodobenzoyl)-DL-aspartic Acid,
N-(3-methylaminocarbonyl-5-acetamido-2.4.6-triiodobenzoyl)-DL-asparagine,
N-(3-methylaminocarbonyl-5-methoxyacetamido-2.4.6-triiodobenzoyl)-L-phenylalanine,
N-(3-methylaminocarbonyl-5-acetamido-2.4.6-triiodobenzoyl)-DL-α-aminobutyric Acid,
N-(3-carboxy-5-acetamido-2.4.6-triiodobenzoyl)-ε-acetyl-L-lysine-amide,
N-(3-methylaminocarbonyl-5-acetamido-2.4.6-triiodobenzoyl)-α-acetyl-L-ornithine,
N-(3-ethanolaminocarbonyl-5-methoxyacetamido-2.4.6-triiodobenzoyl)-glycine,
N-(3-methylaminocarbonyl-5-acetamido-2.4.6-triiodobenzoyl-L-proline,
N-(3-carboxy-5-methoxyacetamido-2.4.6-triiodobenzoyl)-L-leucine Methylamide,
N-(3-carboxy-5-acetamido-2.4.6-triiodobenzoyl)-O-methyl-L-tyrosine-Methylamide.
The following Table 1 lists the significant properties of illustrative compounds of this invention, denoted by A, B, C, D, E, F, G, in comparison with those of the structurally comparable, conventional substance H.
A: n-(3-carboxy-5-acetamido-2,4,5-triiodobenzoyl)-glycine amide.
B: n-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-DL-alanine methylamide.
C: n-(3-carboxy-5-methoxyacetamido-2,4,6-triiodobenzoyl)-glycine methylamide.
D: n-(3-methylaminocarbonyl-5-acetamido-2,4,6-triiodobenzoyl)-sarcosine. E: N-(3-aminocarbonyl-5-acetamido-2,4,6-triiodbenzoyl)-glycine.
F: n-(3-carboxy-5-methoxyacetamido-2,4,6-triiodobenzoyl)-DL-serine methylamide.
G: n-(3-carboxy-5-hydroxyacetamido-2,4,6-triiodobenzoyl)-glycine methylamide.
H: "iotalamat" = 3-acetamido-5-methylcarbamoyl-2,4,6-triiodobenzoic acid (U.S. Pat. No. 3,145,197).
All substances were tested as methylglucamine salts with 200 mg. I/ml. of solution. The intracerebral compatibility was determined on rats in accordance with Valzelli, Med. Exp. 11: 23-26 (1964).
In order to determine the cisternal compatibility, the test compounds were injected in varying doses (0.008 - 0.200 ml./kg.) by means of a Hamilton No. 710 syringe directly into the suboccipital cisterna of rats which were under a slight ether narcosis.
Cerebral compatibility was likewise determined on rats. In an operation under a slight ether narcosis, a catheter was affixed in the left common carotid artery; the distal end of the catheter, after having been passed through the lateral connective tissue of the neck, was fixed in the center of the back. Three hours later, the test compounds were cranially injected in varying doses (14.0 - 26.0 ml./kg.) into the artery.
As a measure of physiological compatibility, the ED50 was determined in each case, i.e., the dose at which an undesired array of neurological symptoms (including convulsions and death) is evoked in 50% of the animals.
TABLE 1 __________________________________________________________________________ ED.sub.50 in mg. I/kg. MYELOGRAPHY ANGIOGRAPHY Intracerebral Compatibility According to Cisternal Cerebral Compound Valzelli Compatibility Compatibility __________________________________________________________________________ A (1) 60.86 (2) 70.72 (1) 10.56 (2) 11.17 B (1) 61.92 (2) 66.30 (1) 10.9 (2) 16.7 C (1) 61.28 (2) 53.97 (1) 10.07 (2) 20.04 D (1) 59.83 (2) 76.21 (1) 10.30 (2) 11.93 (1) 3.38 (2) 3.99 E (1) 56.59 (2) 69.84 (1) 10.56 (2) 14.42 F (1) 59.83 (2) 81.32 (1) 11.8 (2) 22.8 (1) 4.20 (2) 3.78 G (1) 56.59 (2) 62.62 (1) 9.8 (2) 11.8 (1) 3.20 (2) 3.55 __________________________________________________________________________ (1) "Iotalamat" (H) (2) Compounds A - G
It can be seen from Table 1 that the compounds of this invention, especially with respect to their cisternal compatibility, are markedly superior to the conventional compound H.
The compounds of general Formula E of the present invention can be produced by reacting novel compounds of general Formula Z ##SPC3##
wherein ##EQU7## X and Y have the aboveindicated values, with an amino acylating agent of the formula RCO--W, wherein R have the above-indicated value and W represents a carboxylic acid functional group, e.g., a carboxylic acid halide, an acid anhydride, or a carboxylic acid ester. Acylation is effected in the presence of catalytic amounts of a mineral acid, e.g., sulfuric acid or perchloric acid. Suitable acylation solvents are well known in the art and include but are not limited to excess acid anhydride, acid, acid esters or mixtures thereof. Preferred acylating agents are the carboxylic acid halides, preferably in a polar aprotic solvent, e.g., dimethylacetamide.
Compounds of general Formula E wherein X is ##EQU8## and Y is hydroxy can also be prepared by reacting compounds of the general Formula Z' ##SPC4##
Wherein R, R1 and R2 have the above-indicated values with amino acids in the presence of organic or inorganic bases or with amino acid esters, and optionally subsequently saponifying the thus obtained esters. The reaction with amino acids or amino acid esters is preferably conducted in a cyclic ether solvent, e.g., dioxane or tetrahydrofuran.
The compounds of general Formula Z' useful as a starting material are described in German Unexamined Published Application No. 2,031,724.
The compounds of general Formula Z, which represent a particularly important group of starting compounds, can be prepared in accordance with conventional processes.
For example, in order to prepare compounds of Formula Z wherein X is hydroxy group and Y is group ##EQU9## 3-methoxycarbonyl-5-nitrobenzoyl chloride (J. Med. Chem. 6:24 (1963) is reacted with an amino acid amide to the corresponding N-(3-methoxycarbonyl-5-nitrobenzoyl)-amino acid amide (I). The latter is saponified to the acid II in a customary manner, converted into the aminoisophthalic acid monoamino acid amide (III) by reduction (hydrogenation at elevated pressure with Raney nickel as the catalyst), and this product can then be iodated, e.g., with KICl2, to the desired compound IV.
The amino acid amides are obtained in a conventional manner by the reduction of amino acid alkyl esters with ammonia or with the corresponding amines.
The compounds of the general Formula Z wherein X is ##EQU10## and Y is hydroxy can be produced, for example, by reacting 3-methoxycarbonyl-5-nitrobenzoyl chloride (J. Med. Chem. 6:24, 1963) with an amino acid to the corresponding N(3-methoxycarbonyl-5-nitrobenzoyl)-amino acid (VI); thereafter amidating the methoxycarbonyl group to VII, with a correspondingly substituted amine or ammonia; hydrogenating the nitro group; and iodating the amino compound (VIII) to IX.
N-(3-methoxycarbonyl-5-nitrobenzoyl)-amino acid amide (I) can also be obtained by reacting the corresponding amino acid (VI) with an amine, e.g., in accordance with the method used to prepare mixed anhydrides.
The reactions will be explained in greater detail with reference to the following scheme of formulae: ##SPC5##
The novel triiodized isophthalic acid monoamino acid amides of Formula E are valuable contrast agents for radiopaque materials and novel intermediates for the production of radiological contrast substances.
One ore more of the compounds of this invention can be employed in mixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application which do not deleteriously react with the active compounds. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, etc.
For parenteral application, particularly suitable are solutions, preferably aqueous solutions. Ampoules are convenient unit dosages, or multivials containing multiple unit dosages can be used.
For intravenous administration the soluble salts of this invention are preferably used in aqueous solution whereby the concentration of the salts is preferably between about 15 % by volume and about 75 % by volume. Generally the amount of active agent per unit dosage is about 5 to 50 g., preferably 7 to 35 g.
The acids, in the form of their water-soluble physiologically compatible salts, are extraordinarily good radiopaque agents for myelography, urography, and angiography.
The salt solutions are characterized by a relatively low viscosity and can be administered by intravenous injection. The salt solutions are furthermore distinguished by a good circulatory compatibility and a low toxicity.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. In the following examples, the temperatures are set forth in degrees Celsius. Unless otherwise indicated, all parts and percentages are by weight.
The starting compounds can be prepared as follows:
Process 1: Under ice cooling, 378.0 g. (4.5 moles) of sodium bicarbonate is added to 193.3 g. (1.55 moles) of glycine methylamide hydrochloride in 3.75 liters of water. Over a period of 3 hours, 365.4 g. of 3-methoxycarbonyl-5-nitrobenzoyl chloride in 1.3 l. of acetone is added dropwise to this reaction mixture. Thereafter, the mixture is stirred for 11/2 hours at room temperature; the product is vacuum-filtered, washed free of salt with water, and dried under vacuum at 70° C.
Yield: 424 g. For purposes of analysis, the product is recrystallized from methanol or acetonitrile. M.P. 174°-175 °C.
Process 2: 8.5 g. (0.03 mole) of N-(3-metoxycarbonyl-5-nitrobenzoyl-glycine (VIa) dissolved in 130 ml. of absolute tetrahydrofuran, is cooled to -15° C., after the addition of 4.2 ml. of triethylamine, and mixed under agitation with 3 ml. of the ethyl ester of chlorocarbonic acid. The reaction mixture is agitated for about 10 minutes at -10° to -5° C., and a solution of 2.8 ml. of methylamine in 20 ml. of absolute tetrahydrofuran, cooled to -15° C., is gradually added thereto dropwise under agitation. Then, the mixture is stirred for another 30 minutes at -15° C. and subsequently overnight at room temperature; the triethylamine hydrochloride is filtered off, the filtrate concentrated under vacuum, and the residue recrystallized from acetonitrile; yield 4.6 g. m.p. 173°-174° C.
443.0 g. (1.5 moles) of N-(3-metoxycarbonyl-5-nitrobenzoyl-glycine methylamide in 5.5 l. of dioxane is agitated for 2 hours at room temperature with the addition of 3.3 l. of 0.5N sodium hydroxide solution. Thereafter, 400 ml. of water is added to the reaction mixture, the dioxane is distilled off under vacuum, and the acid is precipitated with concentrated hydrochloric acid, vacuum-filtered, washed free of salt with water, and dried under vacuum at 70° C. Yield: 408 g. M.P. 256- 257°C.
449.9 g. (1.6 moles) of N-(3-carboxy-5-nitrobenzoyl)-glycine methylamide in 2 l. of water is dissolved with the addition of 880 ml. of 2N ammonia and hydrogenated at room temperature with 10% Raney nickel as the catalyst at about 120 atmospheres gauge. After separation of the catalyst, the remaining hydrogenation solution is further employed as such for iodation. The free compound can be obtained from the frothy ammonium salt, dissolved in methanol, by precipitation with trifluoroacetic acid.
Yield: 352 g. M.P. 236°-237°C.
A solution of the ammonium salt of N-(3-carboxy-5-aminobenzoyl)-glycine methylamide, produced by hydrogention of 1.6 moles of the corresponding nitro compound, is replenished with water to 140 liters and, under agitation, 3.6 l. of concentrated hydrochloric acid and 3.5 l. of 2N KICl2 solution are added thereto. After three days of agitation, the reaction product is filtered from the precipitate, thoroughly washed with water, then agitated for 2 hours with water, vacuum-filtered, and dried under vacuum at 70° C.
Yield: 910.5 g. M.P. 252°-253°C (under decomposition).
Under agitation and during the course of 21/2 hours, 183.0 g. (0.75 mole) of 3-methoxycarbonyl-5-nitrobenzoyl chloride in 750 ml. of acetone is added dropwise to a solution of 62.0 g. (0.825 mole) of glycine and 189.0 G. of sodium bicarbonate in 3 l. of water. The first-obtained precipitate is gradually dissolved again after an additional three hours of agitation. Thereafter, the reaction mixture is extracted twice with ether, the acqueous phase is acidified with concentrated hydrochloric acid, the thus-precipitated oil is extracted repeatedly with ethyl acetate, and the combined ethyl acetate extracts, after washing with water and drying with sodium sulfate, are mixed with a stoichiometric amount of dicyclohexylamine. After allowing the reaction mixture to stand for some time, it is filtered off from the precipitated dicyclohexylammonium salt (m.p. 204°-205° C. from chloroform/ether), washed several times with ether, and the acid is liberated again by distributing the reaction mixture between ethyl acetate and 2N sulfuric acid. After washing the ethyl phases with water, drying with sodium sulfate, and concentrating under vacuum, 181.0 g. of the above-identified compound is obtained. M.P. 142°-143°C.
15 ml. of liquid methylamine is added at 0° C. to 42.3 g. (0.15 mole) of N-(3-methoxycarbonyl-5-nitrobenzoyl)-glycine (VIa) in 150 ml. of methanol; the reaction mixture is stored for 3 days at room temperature. Then, the mixture is concentrated to dryness under vacuum, and the residue is refluxed with absolute alcohol. After cooling, the reaction mixture is filtered, washed with alcohol and dried under vacuum. Yield: 43.2 g. M.P. 216°-217°C.
In an analogous manner, the other starting compounds are likewise produced. Table 4 indicates the yields and melting points of several compounds I through IV and VI through IX.
TABLE 2 __________________________________________________________________________ --N--A--CO-- | R.sub.3 R.sub.1 R.sub.2 I II III IV % M.P. % M.P. M.P. % M.P. Yield °C. Yield °C. °C. Yield °C.(Z) __________________________________________________________________________ a) Gly H CH.sub.3 96 174-175 97 256-257 236-237 90 252-253 b) DL-Ser H CH.sub.3 71 169-170 82 239-240 223-224 78 259-260 c) Gly H H 86 190-191 90 245-246 231-233 51 248-249 d) DL-Ala H CH.sub.3 62 173-174 97 248-250 217-219 73 208-209 e) Sar H CH.sub.3 91 126-127 85 212-213 Foam 92 238-240 f) β-Ala H CH.sub.3 81 181-182 90 247-248 199-200 80 170/250-252 g) L-Phe H CH.sub.3 90 204-205 99 238-239 235-237 93 281-282 h) L-Pro H CH.sub.3 77 159-160 89 228-229 * 84 248-250 i) GlyGly H CH.sub.3 89 219-220 93 249-250 244-245 52 230-232 k) Gly-L- H CH.sub.3 79 191-192 98 223-225 * 36 228-230 Leu l) Gly 36 194-195 68 227-228 * 73 ˜200 m) Gly H CH.sub.2 CH.sub.2 OH 47 171-172 99 191-192 * 79 201-202 n) Gly CH.sub.3 CH.sub.3 63 174-175 94 236-237 * 62 239-241 o) DL-Abu H CH.sub.3 70 215-216 92 254-256 * 79 220 p) DL-Val H CH.sub.3 73 235-236 98 249-251 * 84 ˜235 r) L-Val- H CH.sub.3 30 308-310 90 292-293 * 87 247-248 L-Val s) N-phenyl- β-Ala H CH.sub.3 77 110-112 96 205-207 * 85 ˜220 __________________________________________________________________________ * Substance processed further without isolation.
TABLE 3 __________________________________________________________________________ --N--A--CO-- | R.sub.3 VI VII VIII IX % M.P. R.sub.1 R.sub.2 % M.P. M.P. % M.P. Yield °C. Yield °C. °C. Yield °C.(Z) __________________________________________________________________________ a) Gly 85 142-143 H CH.sub.3 92 216-217 * 84 265-266 b) Gly H H 100 245-246 * 80 271-272 c) β-Ala H CH.sub.3 89 185-186 * ˜76 190 69 168-169 d) β-Ala H H 62 202-203** * 81 239-241 e) DL-Ser 61 174-175 H CH.sub.3 95 180-182** * 70 247-248 f) DL-Thr 64 168-169 H CH.sub.3 69 190-192** * 95 263-264 g) Sar 80 135-136 H CH.sub.3 97 188-189 * 69 236-237 h) Gly-Gly 93 193-194 H CH.sub.3 70 205-207 * 77 245-246 __________________________________________________________________________ * Substance processed further without isolation. ** As the methylammonium and/or ammonium salt.
a. 629.0 g. (1 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine methylamide (IV a), m.p. 252°-253° C. (decomposition), is dissolved in 1.2 l. of dimethylacetamide and, under cooling and agitation, 170 ml. of acetyl chloride is added dropwise thereto. The reaction mixture is stirred overnight at room temperature, some water is added, and the mixture is concentrated under vacuum. The remaining oil is treated under agitation with 600 ml. of water, thus obtaining a solid precipitate. The product is allowed to stand for some time, the compound is vacuum-filtered, washed thoroughly with water, and then dissolved in 2.5 l. of water with the addition of the stoichiometric amount of 2N ammonia. The solution is treated for 2 hours with activated carbon and finally, after removal of the carbon, the filtrate is acidified with concentrated hydrochloric acid. After allowing the reaction mixture to stand overnight, the product is vacuum-filtered, washed with water, then stirred with water for a certain period of time, again filtered, and dried under vacuum at 70° C.
Yield: 611 g. (91%), m.p. 284°-285° C. (under decomposition).
Analysis: C13 H12 I3 N3 O5 ; (671.0). Calculated: C 23.27 %; H 1.80 %; I 56.74 %; N 6.26 %; E 671. Found: C 23.53 %; H 1.78 %; I 56.69 %; N 6.35 %; E 668.
b. The above-mentioned compound can also be obtained in a conventional manner by acetylation with acetic anhydride in glacial acetic acid in the pressure of concentrated sulfuric acid as the catalyst, with a yield of 52%, m.p. 282-283° C. (under decomposition).
82.4 g. (0.125 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-serine methylamide (IV b), m.p. 259°-260° C. (decomposition), is dissolved in 200 ml. of dimethylacetamide; under agitation, 33.4 ml. of acetyl chloride is added dropwise thereto. The reaction mixture is agitated for 20 hours, mixed with 40 ml. of water, and, after another 30 minutes of agitation, concentrated under vacuum. The residue is stirred overnight with 150 ml. of water, the precipitate is vacuum-filtered, stirred in 150 ml. of 1N sodium hydroxide solution with the addition of 15 ml. of 37% strength sodium hydroxide solution and activated carbon for 2 hours, the activated carbon is removed, and the filtrate is brought to pH 1 with concentrated hydrochloric acid. After allowing the reaction mixture to stand overnight at 0° C., the precipitate is vacuum-filtered, washed with ice water, and dried under vacuum at 70° C.
Yield: 62.0 g., m.p. 276°-277° C. (under decomposition).
Analysis: C14 H14 I3 N3 O6 ; (701.01). Calculated: C 23.99 %; H 2.01 %; I 54.31 %; E 701.0. Found: C 24.30 %; H 2.40 %; I 54.27 %; E 696.0.
Under agitation and cooling with water, 13.5 ml. of acetyl chloride is added dropwise to 40.0 g. (65 millimoles) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine amide (IV c), m.p. 248°-249° C. (decomposition), in 80 ml. of dimethylacetamide. Then, the reaction mixture is stirred at room temperature for 11/2 hours, another 2 ml. of acetyl chloride is added thereto, and the mixture stirred for another hour. After the addition of 10 ml. of water, the reaction mixture is concentrated under vacuum, 70 ml. of water is added to the residue, and the mixture is stirred for 16 hours. The precipitate is vacuum-filtered and washed free of salt with water.
Yield: 40.0 g. (93.7%), m.p. 273°-274° C. (under decomposition).
Analysis: C12 H10 I3 N3 O5 ; (657.0). Calculated: C 21.93 %; H 1.54 %; N 6.39 %; I 57.95 %; E 657. Found: C 21.87 %; H 2.08 %; N 5.89 %; I 57.80 %; E 650.
Analogously to Example 1, 95.2 g. (81.8%) of N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-DL-alanine methylamide is obtained from 190.3 g. (0.17 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-alanne methylamide (IV d), m.p. 208°-209° C. (decomposition), in 210 ml. of dimethylacetamide and 61.2 ml. of acetyl chloride. The melting point of the product is 273°-274° C. (under decomposition).
Analysis: C14 H14 I3 N3 O5 ; (685.0). Calculated: C 24.53 %; H 2.06 %; N 6.13 %; I 55.58 %; E 685. Found: C 24.70 %; H 2.44 %; N 6.14 %; I 55.58 %; E 689.
Analogously to Example 3, 71.5 g. (74.5%) of N-3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-sarcosine methylamide, m.p. 270°-271° C. (under decomposition) is obtained from 90 g. (0.14 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-sarcosine methylamide (IV e), m.p. 238°-240° C. (decomposition) in 170 ml. of dimethylacetamide and 27.4 ml. of acetyl chloride.
Analysis: C.sub. 14 H14 I3 N3 O5 ; (685.0). Calculated I 55.58 %; E 685. Found: I 55.54 %; E 678.
99.5 g. (0.15 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-β-alanine methylamide . 1.1 H2 O (IV f), m.p. 250°-252° C. (decomposition) in 190 ml. of dimethylacetamide yield, after reaction with 40.0 ml. of acetyl chloride analogously to Example 1, 60.4 g. (58.8%) of the desired compound. A sample for analysis is purified in alcohol by way of the dimethylammonium salt; m.p. 288°-289° C. (under decomposition).
Analysis: C14 H14 I3 N3 O5 ; (685.0). Calculated I 55.58 %; E 685. Found: I 55.55 %; E 695.
Analogously to Example 1, 67.5 g. (88.7%) of the desired compound, m.p. 276°-277° C. (under decomposition) is obtained from 71.9 g. (0.1 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-L-phenylalanine methylamide (IV g), m.p. 281°-282° C. (decomposition), in 120 ml. of dimethylacetamide with 17 ml. of acetyl chloride.
Analysis: C20 H18 I3 N3 O5 ; (761.1). Calculated: C 31.56 %; H 2.38 %; N 5.52 %; I 50.0 %; E 761. Found: C 31.47 %; H 2.55 %; N 5.53 %; I 50.0 %; E 764.
In accordance with Example 1, 36.5 g. (64%) of the desired compound, m.p. 245°-247° C. (under decomposition), is produced from 53.5 g. (0.080 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-L-proline methylamide (IV h) in 96 ml. of dimethylacetamide with 13.6 ml. of acetyl chloride.
Analysis: C16 H16 I3 N.sub. 3 O5 ; (711.1). Calculated: I 53.55 %; E 711. Found: I 53.64 %; E 710.
From N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycylglycine methylamide (IV i), m.p. 230°-232°C. (decomposition), in dimethylacetamide, 34.3% of the desired compound, m.p. 253°-255° C. (under decomposition) is obtained with the addition of acetyl chloride, as described in Example 1, and after recrystallization from aqueous acetonitrile.
Analysis: C15 H15 I3 N4 O6 ; (728.1). Calculated: N 7.70 %; I 52.3 %. Found: N 7.68 %; I 52.1.
Analogously to Example 1, the desired compound is produced from the corresponding 5-amino compound (IV k), m.p. 228°-230° C. (decomposition).
At maximally 10° C., 29.0 ml. of thionyl chloride is added dropwise under agitation to 28.2 ml. of methoxyacetic acid in 100 ml. of dimethylacetamide within 40 minutes. After, at 0° C., the reaction mixture has been agitated for another 2 hours, 63.0 g. (0.1 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine methylamide (IV a), m.p. 252°-253° C. (decomposition), in 100 ml. of dimethylacetamide is added dropwise under agitation to the reaction mixture at maximally 8° C. during the course of one hour. Then, the solution is agitated overnight. After the addition of 5 ml. of water, the mixture is concentrated under vacuum, the residue is stirred with 700 ml. of water, the precipitate is vacuum-filtered, carefully washed with water, and, while still moist, reprecipitated from dilute ammonia with concentrated hydrochloric acid. After allowing the mixture to stand for some time, the acid is vacuum-filtered, washed well with water, stirred with fresh water, and, after another filtering step, dried under vacuum at 70° C.
Yield: 54.0 g. (77%) of a product which is uniform as determined by thin-layer chromatography and has a melting point of 226°-228° C. (under decomposition).
Analysis: C14 H14 I3 N3 O6 ; (701.0). Calculated: I 54.3 %; E 701. Found: I 54.3 %; E 706.
Analogously to Example 11, 51.5 g. (65%) of the desired substance, m.p. 250°-252° C. (under decomposition); is obtained from 71.9 g. (0.1 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-L-phenylalanine methylamide (IV g), m.p. 282°-282° C.
Analysis: C21 H20 I3 N3 O6 ; (791.1). Calculated: I 48.12 % ; E 791. Found: I 48.02 %; E 796.
Under agitation and water cooling, 31.5 ml. of valeroyl chloride is added dropwise to 45.8 g. (0.073 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzyl)-glycine methylamide (Iv a), m.p. 252°-253° C. (under decomposition), in 120 ml. of dimethylacetamide. After agitating the reaction mixture overnight at room temprature, the product is precipitated by adding water; then, the product is vacuum-filtered and purified by dissolving the corresponding sodium salt and separation of the free acid by the addition of a mineral acid.
Yield: 41.8 g. (80.1%), m.p. 258°-260° C. (under decomposition).
Analysis: C16 H18 I3 N3 O5 ; (713.1). Calculated: I 53.4 %; E 713. Found: I 53.1 %; E 706.
Under agitation, 20 ml. of acetyl chloride is added dropwise to 66.0 g. (0.015 mole) of N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-glycine (IX a), m.p. 256°-266° C., in 140 ml. of dimethylacetamide, and the mixture is stirred overnight. After the addition of a small amount of water, the mixture is agitated for another 2 hours, concentrated under vacuum, and the oily residue is stirred with 50 ml. of water for 16 hours. Then, the precipitate is vacuum-filtered, washed with water, the compound is dissolved with 2N NH4 OH to form a neutral solution, treated with activated carbon, and, after the removal of the carbon, acidified with concentrated hydrochloric acid. After allowing the reaction mixture to stand for about 20 hours at room temperature, it is filtered, washed free of salt with water, and dried under vacuum at 70° C.
Yield: 45.6 g. (64.7), m.p. 289°-291° C. (under decomposition).
Analysis: C13 H12 N3 I3 O5 ; (671.0). Calculated: I 56.74 % ; E 671. Found: I 56.66 %; E 671.
Analogously, N-(3-methylaminocarbonyl-5-propionylamido-2,4,6-triiodobenzoyl)-glycine is prepared with propionyl chloride. This product has a melting point of 284°-286° C. (under decomposition).
From 100.0 g. (0.155 mole) of N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-β-alanine (IX c), m.p. about 190° C., in 190 ml. of dimethylacetamide, 70.1 g. (66.0%) of the above product, m.p. 295°-297°C. (under decomposition) is obtained with the addition of 28.7 ml. of acetyl chloride analogously to Example 14 and after reprecipitation from aqueous ammonia with hydrochloric acid.
Analysis: C14 H14 I3 N3 O5 ; (685.0). Calculated: I 55.58 %; E 685. Found: I 55.56 %; E 681.
0.1 mole of 3-methylaminocarbonyl-5-acetamido-2,4,6-triiodobenzoyl chloride (compound of general Formula Z' with R1 = H, R2 = R3 = CH3) and 0.2 mole of glycine methyl ester hydrochloride are heated in 700 ml. of dioxane, with the addition of 0.3 mole of triethylamine, for 4 hours to 60° C., and then agitated at room temperature for 15 hours. The product is filtered off from the precipitate, washed with water, and dried at 60° C. under vacuum, thus obtaining 47.3 g. (69%) of the desired compound having a melting point of 309°-311° C. (under decomposition).
Analysis: C14 H14 I3 N3 O5 ; (685.0). Calculated; C 24.55 %; H 2.06 %; I 55.58 %; N 6.13 %. Found: C 24.27 %; H 2.18 %; I 55.47 %; N 6.00.
The methyl ester obtained according to (a) is refluxed for 2 hours in alcohol, adding an excess of 1N sodium hydroxide solution; the product is precipitated with concentrated hydrochloric acid.
Yield: 65%, m.p. 288°-290° C. (under decomposition).
The substance is identical to the compound according to Example 14, as determined by thin-layer chromatography and IR spectrum.
The compound is obtained analogously to Example 1 by acetylation of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine morpholide (IV l), m.p. about 200° C. (under decomposition), in dimethylacetamide.
Yield: 56%, m.p. 278°-279° C. (under decomposition).
Analysis: C16 H16 I3 N3 O6 ; (727.0). Calculated: C 26.43 %; H 2.22 %; I 52.37 %; N 5.78 %; E 727. Found: C 26.59 %; H 2.31 %; I 52.21 %; N 5.97 %; E 716.
This compound is prepared analogously to Example 1 from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine ethanolamide (IV m), m.p. 201°-202° C. (under decomposition). After concentrating the dimethylacetamide solution under vacuum, the residue is stored with saturated soda solution for 48 hours at room temperature, the acid is precipitated with concentrated hydrochloric acid, and once again purified by reprecipitation from aqueous ammonia with a mineral acid.
Yield: 59%, m.p. 271°-272° C. (under decomposition).
Analysis: C14 H14 I3 N3 O6 ; (701.0). Calculated: C 23.99 %; H 2.01 %; I 54.31 %; N 5.99 %; E 701. Found: C 24.09 %; H 2.06 %; I 54.04 %; N 5.99 %; E 696.
N-(3-Carboxy-5-acetamido-2,4,6-triiodobenzoyl)-glycine Dimethylamide
Analogously to Example 1, N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine dimethylamide (IV n), m.p. 239°-241° C. (under decomposition) is acetylated with acetyl chloride in dimethylacetamide.
Yield: 62%, m.p. 251°-253° C. (under decomposition).
Analysis; C14 H14 I3 N3 O5 ; (685.0). Calculated: C 24.55 %; H 2.06 %; I 55.58 % ; N 6.13 % ; E 685. Found: C 24.38 %; H 2.44 %; I 55.52 %; N 6.06 %; E 677.
The compound is obtained in accordance with Example 14 from N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-sarcosine (IX g), m.p. 228°-229° C. (under decomposition), and acetyl chloride in dimethylacetamide; this product has a melting point of 287°-289° C. (under decomposition).
Analysis: C14 H14 I3 N3 O5 ; (685.0). Calculated: I 55.58 %; E 685. Found: I 55.28 %; E 675.
This compound is produced analogously to Example 14 from 61.5 g. (0.1 mole) of N-(3-aminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-glycine (IX b), m.p. 271°-272° C. (under decomposition ), in 120 ml. of dimethylacetamide and 22 ml. of acetyl chloride.
Yield: 54.8 g. (83.4%), m.p. about 310° C. (under decomposition).
Analysis: C12 H10 I3 N3 O5 ; (657.0). Calculated: C 21.93 %; H 1.54 %; I 57.95 %; N 6.39 %; E 657. Found: C 22.21 %; H 1.71 %; I 57.71 %; N 6.47 %; E 656.
According to Example 11, the above compound is obtained from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-serine methylamide (IV b), m.p. 259°-260° C. (under decomposition) and methoxyacetic acid/thionyl chloride in dimethylacetamide.
Yield: 72%, m.p. 270°-272° C. (under decomposition).
Analysis: C15 H16 I3 N3 O7 ; (731.0). Calculated: C 24.64 %; H 2.21 %; I 52.08 %; N 5.75 %; E 731. Found: C 24.90 %, H 2.36 %; I 52.07 %; N 5.93 %; E 726.
At temperatures of maximally 10° C., 44 ml. of acetoxyacetyl chloride is gradually added dropwise under agitation to a solution of 63 g. (0.1 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine methylamide (IV a), m.p. 252°-253° C. (under decomposition) in 100 ml. of dimethylacetamide. After 8 hours of agitation at room temperature, 500 ml. of water is added to the reaction mixture, the thus-precipitated product is filtered off, after allowing the mixture to stand for some time at 0° C., thoroughly washed, and dissolved in 150 ml. of 2N sodium hydroxide solution and 500 ml. of water. The solution is heated or 1 hour on a steam bath under agitation. After cooling, another 500 ml. of water is added, and the product is precipitated with concentrated hydrochloric acid. After vacuum-filtering, thorough washing, and drying under vacuum, 51 g. (74.2%) of a crude product is obtained. For further purification, the ammonium salt, isolated from methanol, is converted in an aqueous solution with concentrated hydrochloric acid, into the free acid, m.p. 227°-229° C. (under decomposition).
Analysis: C13 H12 I3 N3 O6 ; (687.0). Calculated: C22.73 %; H 1.76 %; I 55.42 %; N 6.12 %; E 687. Found: C 22.98 %; H 176 %; I 55.09 %; N 6.22 %; E 698.
This compound is produced analogously to Example 2 from N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-DL-threonine (IX f), m.p. 263°-264° C. (under decomposition) and acetyl chloride in dimethylacetamide.
Yield: 58.1%, m.p. 264°-265° C. (under decomposition).
Analysis: C15 H16 I3 N3 O6 ; (715.0). Calculated: C 24.19 %; H 2.26 %; I 53.24 %; N 5.88 %; E 715. Found: C 24.29 %; H 2.39 %; I 53.25 %; N 5.77 %; E 713.
This compound, m.p. 277°-279°C. (under decomposition) is produced analogously to Example 2 from the corresponding triiodoamino compound (IX d), m.p. 239°-241° C. (under decomposition), and acetyl chloride in dimethylacetamide.
Analysis: C13 H12 I3 N3 O5 ; (671.0). Calculated: C 23.27 %; H 1.80 %; I 56.74 %; N 6.26 %; E 671. Found: C 23.07 %; H 2.10 %; I 56.79 %; N 6.29 %; E 672.
This compound is produced analogously to Example 2 by acetylation of the 5-amino compound (IX e), m.p. 247°-248° C. (under decomposition), with acetyl chloride in dimethylacetamide.
Yield: 75.4%, m.p. 257°-259° C. (under decomposition).
Analysis: C14 H14 I3 N3 O6 ; (701.0). Calculated: C 23.99 %; H 2.01 %; I 54.31 %; N 6.00 %. Found: C 23.68 %; H 2.32 %; I 54.64 %; N 6.13.
This compound is obtained as described in Example 11 from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-alanine methylamide (IV d), m.p. 208°-209° C. (under decomposition), and methoxyacetyl chloride.
Yield: 71%, m.p. 239°-241° C. (under decomposition).
Analysis: C15 H16 I3 N3 O6 ; (715.0). Calculaed: C 25.19 %, H 2.26 %; N 5.88 %; I 53.24 %; E 715. Found: C 24.70 %; H 2.63 %; N 5.69 %; I 53.51 %; E 712.
Analogously to Example 1, this compound is produced from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl-DL-α-aminobutyric acid methylamide (IV o), m.p. about 220° C. (under decomposition), and acetyl chloride.
Yield: 59%, m.p. 249°-251° C. (under decomposition).
Analysis: C15 H16 I3 N3 O5 ; (699.0). Calculated: N 6.01 %; I 54.46 %; E 699 . Found: N 5.99 %; I 54.13 %; E 698.
This compound is produced analogously to Example 11 by reacting N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-α-aminobutyric acid methylamide (IV o), m.p. about 220° C. (under decomposition), with methoxyacetic acid/thionyl chloride.
Yield: 55%, m.p. 270°-272° C. (under decomposition).
Analysis: C16 H18 I3 N6 O6 ; (729.0). Calculated: C26.36 %; H 2.49 %; N 5.76 %; I 52.22 %; E 729. Found: C 26.52 %; H 2.75 %; N 6.00 %; I 51.64 %; E
The above compound is produced in accordance with Example 11 from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-sarcosine methylamide (IV e), m.p. 238°-239° C. (under decomposition), and in methoxyacetyl chloride.
Yield: 41%, m.p. 267°-269° C. (under decomposition).
Analysis: C15 H16 I3 N3 O6 ; (715.0). Calculated: I 53.24 %; E 715. Found: C 53.24 %; E 725.
As described in Example 1, N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-valine methylamide (IV p), m.p. about 235° C. (under decomposition), is reacted with acetyl chloride.
Yield: 82%, m.p. 259°-261° C. (under decomposition).
Analysis: C16 H18 I3 N3 O5 ; (713.0). Calculated: C 26.95 %; H 2.55 %; N 5.89 %; I 53.39 %; E 713. Found: C 26.40 %; H 3.01 %; N 5.73 %; I 52.93 %; E 717.
Analogously to Example 11, the above compound is prepared from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-valine methylamide (IV p), m.p. about 235° C (under decomposition), and methoxyacetyl chloride.
Yield: 65%, m.p. 285°-286° C. (under decomposition).
Analysis: C17 H20 I3 N3 O6 ; (743.1). Calculated: C 27.48 %; H 2.71 %; N 5.66 %; I 51.23 %; E 743. Found: C 27.77 %; H 3.09 %; N 5.86 %; I 51.19 %; E 745.
This compound is obtained analogously to Example 1 by acetylation of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-L-valyl-L-valine methylamide (IV r), m.p. 247°-248° C. (under decomposition).
Yield: 67%, m.p. 255°-257° C. (under decomposition).
Analysis: C21 H27 I3 N4 O6 ; (812.2). Calculated: C31.05 %; H 3.35 %; N 6.90 %; I 46.88 %; E 818. Found: C 30.07 %; H 3.63 %; N 6.79 %; I 46.37 %; E 815.
Analogously to Example 1, the above compound is produced from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-N-phenyl-β-alanine methylamide (IV s), m.p. about 220° C. (under decomposition), and acetyl chloride.
Yield: 53%, m.p. 232°-234° C. (under decomposition).
Analysis: C20 H18 I3 N3 O5 ; (761.1). calculated: I 50.02 %; E 761. Found: I 49.01 %; E 769.
Analogously to Example 11, this compound is obtained from N-(3-aminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-β-alanine (IX c), m.p. about 190° C. (under decomposition), and methoxyacetic acid/thionyl chloride.
Yield: 70%, m.p. 284°-285° C. (under decomposition).
Analysis: C14 H14 I3 N3 O6 ; (701.0). Calculated: C 23.99 %; H 2.01 %; N 6.00 %; I 53.31 %; E 701. Found: C 23.80 %; H 2.52 %; N5.81 %; I 54.22 %; E 7.1.
As described in Example 11, this compound is obtained from N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-glycine (IX a), m.p. 265°-266° C. (under decomposition), and methoxyacetyl chloride.
Yield: 55%, m.p. 310°-312° C. (under decomposition).
Analysis: C14 H14 I3 N3 O6 ; (701.0). Calculated: C 23.99 %; H 2.01 %; N 6.00 %; I 54.31 %; E 7.1. Found: C 24.05 %; H 2.00 %; N 6.00 %; I 54.28 %; E 690.
Analogously to Example 23, this compound is produced from N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-glycine (IX a), m.p. 265°-266° C., and acetoxyacetyl chloride with subsequent saponification of the acetoxyacetyl residue.
Melting point of the product: 293°-295° C. (under decomposition).
Analysis: C13 H12 I3 N3 O6 ; (687.0). Calculated: C 22.73 %; H 1.76 %; N 6.12 %; I 55.42 %. Found: C22.35 %; H 1.88 %; N 5.98 %; I 55.32.
As described in Example 14, this compound is produced from N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-glycylglycine (IX h), m.p. 245°-246° C. (under decomposition), and acetyl chloride in dimethylacetamide.
Yield: 41%, m.p. 241°-243° C. (under decomposition).
Analysis: C15 H15 I3 N4 O6 ; (728.0). Calculated: I 52.29 %; E 728. Found: I 52.15 %; E 725.
The above compound is obtained analogously to Example 11 by the methoxyacetylation of N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-sarcosine (IX g), m.p. 236°-237° C. (under decomposition), with methoxyacetyl chloride.
Yield: 76%, m.p. 299°-301° C. (under decomposition).
Analysis: C15 H16 I3 N3 O6 ; (715.0). Calculated: I 53.24 %; E 715. Found: I 52.93 %; E 710.
Analogously to Example 11, this compound is prepared from N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-DL-serine (IX e), m.p. 247°-248° C. (under decomposition), and methoxyacetic acid/thionyl chloride.
Melting point of this product: 269°-271° C. (under decomposition).
Analysis: C15 H16 I3 N3 O7 ; (731.0). Calculated: N 5.75 %; I 52.08 %; E 731. Found: N5.72 %; I 51.65 %; E 730.
Preparation of a ready-for-use methylglucamine salt solution:
N-(3-Carboxy-5-acetamido-2,4,6-triidobenzoyl)- glycine methylamide 669.2 g. N-Methylglucamine 194.5 g. Disodium edetate 0.1 g. Twice-distilled water ad 1000.0 ml.
The solution is filled into ampoules or "multivials" and sterilized at 120° C. This solution contains 380 mg. I/ml.
Preparation of a ready-for-use sodium salt solution: N-(3-Carboxy-5-acetamido-2,4,6-triiodobenzoyl)-
N-(3-Carboxy-5-acetamido-2,4,6-triidobenzoyl)- glycine methylamide 669.2 g. Sodium hydroxide 39.9 g. Disodium edetate 0.1 g. Twice-distilled water ad 1000.0 ml.
The solution is filled into ampoules or multivials and sterilized at 120° C. This solution contains 380 mg. I/ml.
Preparation of a ready-for-use methylglucamine salt solution:
N-(3-Carboxy-5-acetamido-2,4,6-triidobenzoyl)- DL-serine methylamide 699.2 g. N-Methylglucamine 194.5 g. Disodium edetate 0.1 g. Twice-distilled water ad 1000.0 ml.
The solution is filled into ampoules or multivials and sterilized at 120° C. This solution contains 380 mg. I/ml.
Preparation of a ready-for-use methylglucamine salt solution:
N-(3-Carboxy-5-methoxyacetamido-2,4,6-triidobenzoyl)- DL-serine methylamide 537.6 g. N-Methylglucamine 143.6 g. Disodium edetate 0.1 g. Twice-distilled water ad 1000.0 ml.
This solution is filled into ampoules or multivials and sterilized at 120° C. This solution contains 280 mg. I/ml.
The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Claims (11)
1. A triiodoisophthalic acid monoamino acid amide of the formula ##SPC6##
wherein ##EQU11## is divalent amino lower alkanoyl derived from a naturally occurring amino acid;
R is alkyl, hydroxyalkyl or alkoxyalkyl of 1-6 carbon atoms;
R1 and R2 are each hydrogen, alkyl of 1-6 carbon atoms or hydroxyalkyl of 2-6 carbon atoms
and the physiologically acceptable salts thereof.
2. A compound according to claim 1 wherein said amino acid is a monoaminomonocarboxylic acid or a heterocyclic amino acid.
3. A claim according to claim 1 wherein one of R1 R2 is hydrogen.
4. A compound according to claim 1 selected from the group consisting of N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-glycine methylamide; N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-glycine amide; N-(3-carboxy-5-valeroylamino-2,4,6-triiodobenzoyl)-glycine methylamide; N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-glycine ethanolamide; N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-glycine dimethylamide;
5. A compound according to claim 1 selected from the group consisting of N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-sarcosine methylamide; and N-(3-carboxy-5-methoxyacetamido-2,4,6-triiodobenzoyl)-sarcosine methylamide.
6. A compound according to claim 1 selected from the group consisting of N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-DL-serine methylamide; and N-(3-carboxy-5-methoxyacetamido-2,4,6-triiodobenzoyl)-DL-serine methylamide.
7. A compound according to claim 1 selected from the group consisting of N-(3-carboxy-5-methoxyacetamido-2,4,6-triiodobenzoyl)-DL-valine methylamide and N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-DL-valine methylamide.
8. A compound according to claim 1 selected from the group consisting of N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-DL-alanine methylamide; N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-β-alanine methylamide; N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-N-phenylβ-alanine methylamide; and N-(3-carboxy-5-methoxyacetamido-2,4,6-triiodobenzoyl)-DL-alanine methylamide.
9. A compound according to claim 1 selected from the group consisting of N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-L-phenylalanine methylamide; N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-L-proline methylamide; and N-(3-carboxy-5-methoxyacetamido-2,4,6-triiodobenzoyl)-L-phenylalanine methylamide.
10. A compound according to claim 1 selected from the group consisting of N-(3-carboxy-5-acetamido-2,4,6-triiodobenzoyl)-DL-α-aminobutyric acid methylamide and N-(3-carboxy-5-methoxyacetamido-2,4,6-triiodobenzoyl)-DL-α-aminobutyric acid methylamide.
11. A compound according to claim 1, wherein R3 is hydrogen.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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US05/555,043 US4032567A (en) | 1972-02-16 | 1975-03-03 | Triiodoisophthalic acid monoamino acid amides, process for the preparation thereof, and use thereof as x-ray contrast media |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DT2207950 | 1972-02-16 | ||
DE2207950A DE2207950C3 (en) | 1972-02-16 | 1972-02-16 | Triiodoisophthalic acid monoamino acid amides, process for their preparation and X-ray contrast media containing these compounds |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US05/555,043 Division US4032567A (en) | 1972-02-16 | 1975-03-03 | Triiodoisophthalic acid monoamino acid amides, process for the preparation thereof, and use thereof as x-ray contrast media |
Publications (1)
Publication Number | Publication Date |
---|---|
US3953501A true US3953501A (en) | 1976-04-27 |
Family
ID=5836524
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US05/331,110 Expired - Lifetime US3953501A (en) | 1972-02-16 | 1973-02-09 | Triiodoisophthalic acid monoamino acid amides |
Country Status (25)
Country | Link |
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US (1) | US3953501A (en) |
JP (2) | JPS5741460B2 (en) |
AR (2) | AR209257A1 (en) |
AT (1) | AT319464B (en) |
AU (1) | AU474420B2 (en) |
BE (1) | BE795555A (en) |
CA (1) | CA987325A (en) |
CH (2) | CH576422A5 (en) |
CS (2) | CS182780B2 (en) |
DD (1) | DD103890A5 (en) |
DE (1) | DE2207950C3 (en) |
DK (1) | DK135484C (en) |
ES (1) | ES411117A1 (en) |
FI (1) | FI55294C (en) |
FR (1) | FR2181737B1 (en) |
GB (1) | GB1428985A (en) |
HU (1) | HU165260B (en) |
IL (1) | IL41556A (en) |
IT (1) | IT1048111B (en) |
NL (1) | NL7302174A (en) |
NO (1) | NO138168C (en) |
SE (1) | SE410597B (en) |
SU (2) | SU563912A3 (en) |
YU (1) | YU36154B (en) |
ZA (1) | ZA731089B (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4021481A (en) * | 1969-06-27 | 1977-05-03 | Nyegaard & Co. A/S | Amido derivatives of 2,4,6-triiodobenzoic acids containing at least one N-hydroxyalkyl and at least two hydroxyl groups |
US4139605A (en) * | 1977-03-28 | 1979-02-13 | Bracco Industria Chimica S.P.A. | Water-soluble, non-ionizing, radiopaque compounds and contrast compositions containing the same |
US4264572A (en) * | 1978-11-30 | 1981-04-28 | Schering Aktiengesellschaft | X-ray contrast media |
US4283381A (en) * | 1979-07-12 | 1981-08-11 | Schering Aktiengesellschaft | Triiodinated aminoacetamido isophthalamide x-ray contrast agents |
US4307072A (en) * | 1976-03-12 | 1981-12-22 | Mallinckrodt, Inc. | N-Triiodobenzoylaminoacyl polyhydroxic amines |
US4314055A (en) * | 1975-09-29 | 1982-02-02 | Mallinckrodt, Inc. | 3,5-Disubstituted-2,4,6-triiodoanilides of polyhydroxy-monobasic acids |
WO1985001727A1 (en) * | 1983-10-20 | 1985-04-25 | Biophysica Foundation | Novel synthetic methods for non-ionic radiographic contrast media |
US5866100A (en) * | 1995-12-19 | 1999-02-02 | Bracco Research S.A. | Compositions for imaging of the gastrointestinal tract |
WO2000042010A1 (en) * | 1999-01-12 | 2000-07-20 | University Of North Carolina At Chapel Hill | Contrast media for angiography |
WO2024093387A1 (en) * | 2022-11-01 | 2024-05-10 | 科睿驰(深圳)医疗科技发展有限公司 | Contrast compound and method for preparing same, and imageable embolization material and method for preparing same |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1488903A (en) * | 1974-05-31 | 1977-10-19 | Guerbet Sa | X-ray contrast media |
JP2568166B2 (en) * | 1982-10-01 | 1996-12-25 | ニユコメド・イメージング・アクシェセルカペト | X-ray contrast agent |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA616717A (en) * | 1961-03-21 | Distelmaier Alfred | Halogenated aminoisophthalic acids | |
GB867880A (en) * | 1957-03-06 | 1961-05-10 | Schering Ag | N-acyl derivatives of (3:5-diamino-2:4:6-triiodobenzoyl)-amino acids and x-ray contrast media containing the same |
US3009952A (en) * | 1957-04-17 | 1961-11-21 | Sterling Drug Inc | Preparation of halogenated isophthalic acids |
US3102880A (en) * | 1960-09-06 | 1963-09-03 | Mallinckrodt Chemical Works | Isophthaloylbis-amino acid compounds |
US3145197A (en) * | 1961-06-26 | 1964-08-18 | Mallinckrodt Chemical Works | 5-acetamido-nu-alkyl-2, 4, 6-trhodoiso-phthalamic acid compounds |
US3453322A (en) * | 1965-03-31 | 1969-07-01 | Chemie Linz Ag | 2,4,6-triiodo-isophthalic acid amides |
US3622616A (en) * | 1967-07-10 | 1971-11-23 | Lab Andre Guerbet | New benzoic acid derivatives |
US3701771A (en) * | 1969-06-27 | 1972-10-31 | Nyegaard & Co As | N-(2,4,6-triiodobenzoyl)-sugar amines |
-
0
- BE BE795555D patent/BE795555A/en not_active IP Right Cessation
-
1972
- 1972-02-16 DE DE2207950A patent/DE2207950C3/en not_active Expired
- 1972-12-27 DD DD167918A patent/DD103890A5/xx unknown
-
1973
- 1973-01-05 SU SU7301873501A patent/SU563912A3/en active
- 1973-01-26 FI FI220/73A patent/FI55294C/en active
- 1973-01-30 DK DK50273A patent/DK135484C/en active
- 1973-01-30 ES ES411117A patent/ES411117A1/en not_active Expired
- 1973-02-01 CS CS7300000781A patent/CS182780B2/en unknown
- 1973-02-01 CS CS7600002559A patent/CS182796B2/en unknown
- 1973-02-05 AU AU51814/73A patent/AU474420B2/en not_active Expired
- 1973-02-05 YU YU276/73A patent/YU36154B/en unknown
- 1973-02-09 US US05/331,110 patent/US3953501A/en not_active Expired - Lifetime
- 1973-02-12 GB GB682273A patent/GB1428985A/en not_active Expired
- 1973-02-14 AT AT130273A patent/AT319464B/en not_active IP Right Cessation
- 1973-02-15 SE SE7302156A patent/SE410597B/en unknown
- 1973-02-15 FR FR7305347A patent/FR2181737B1/fr not_active Expired
- 1973-02-15 NO NO610/73A patent/NO138168C/en unknown
- 1973-02-15 HU HUSCHE424*1A patent/HU165260B/hu unknown
- 1973-02-16 JP JP48019136A patent/JPS5741460B2/ja not_active Expired
- 1973-02-16 CH CH213476A patent/CH576422A5/xx not_active IP Right Cessation
- 1973-02-16 IT IT20486/73A patent/IT1048111B/en active
- 1973-02-16 ZA ZA731089A patent/ZA731089B/en unknown
- 1973-02-16 IL IL41556A patent/IL41556A/en unknown
- 1973-02-16 CA CA163,941A patent/CA987325A/en not_active Expired
- 1973-02-16 CH CH227873A patent/CH590823A5/xx not_active IP Right Cessation
- 1973-02-16 AR AR246650A patent/AR209257A1/en active
- 1973-02-16 NL NL7302174A patent/NL7302174A/xx not_active Application Discontinuation
-
1974
- 1974-01-01 AR AR253241A patent/AR207951A1/en active
- 1974-07-17 SU SU2043817A patent/SU555846A3/en active
-
1982
- 1982-01-22 JP JP57007722A patent/JPS6059224B2/en not_active Expired
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA616717A (en) * | 1961-03-21 | Distelmaier Alfred | Halogenated aminoisophthalic acids | |
GB867880A (en) * | 1957-03-06 | 1961-05-10 | Schering Ag | N-acyl derivatives of (3:5-diamino-2:4:6-triiodobenzoyl)-amino acids and x-ray contrast media containing the same |
US3009952A (en) * | 1957-04-17 | 1961-11-21 | Sterling Drug Inc | Preparation of halogenated isophthalic acids |
US3102880A (en) * | 1960-09-06 | 1963-09-03 | Mallinckrodt Chemical Works | Isophthaloylbis-amino acid compounds |
US3145197A (en) * | 1961-06-26 | 1964-08-18 | Mallinckrodt Chemical Works | 5-acetamido-nu-alkyl-2, 4, 6-trhodoiso-phthalamic acid compounds |
US3453322A (en) * | 1965-03-31 | 1969-07-01 | Chemie Linz Ag | 2,4,6-triiodo-isophthalic acid amides |
US3622616A (en) * | 1967-07-10 | 1971-11-23 | Lab Andre Guerbet | New benzoic acid derivatives |
US3701771A (en) * | 1969-06-27 | 1972-10-31 | Nyegaard & Co As | N-(2,4,6-triiodobenzoyl)-sugar amines |
Non-Patent Citations (2)
Title |
---|
Chemical Abstracts, Vol. 75, 1440238, (1971), (Abstract of Norw. 122,430, June 28, 1971). * |
Chemical Abstracts, Vol. 77, 92871a, (1972), (Abstract of Fr. 2,085,636, Feb. 4, 1972). * |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4021481A (en) * | 1969-06-27 | 1977-05-03 | Nyegaard & Co. A/S | Amido derivatives of 2,4,6-triiodobenzoic acids containing at least one N-hydroxyalkyl and at least two hydroxyl groups |
US4314055A (en) * | 1975-09-29 | 1982-02-02 | Mallinckrodt, Inc. | 3,5-Disubstituted-2,4,6-triiodoanilides of polyhydroxy-monobasic acids |
US4307072A (en) * | 1976-03-12 | 1981-12-22 | Mallinckrodt, Inc. | N-Triiodobenzoylaminoacyl polyhydroxic amines |
US4139605A (en) * | 1977-03-28 | 1979-02-13 | Bracco Industria Chimica S.P.A. | Water-soluble, non-ionizing, radiopaque compounds and contrast compositions containing the same |
US4264572A (en) * | 1978-11-30 | 1981-04-28 | Schering Aktiengesellschaft | X-ray contrast media |
US4283381A (en) * | 1979-07-12 | 1981-08-11 | Schering Aktiengesellschaft | Triiodinated aminoacetamido isophthalamide x-ray contrast agents |
WO1985001727A1 (en) * | 1983-10-20 | 1985-04-25 | Biophysica Foundation | Novel synthetic methods for non-ionic radiographic contrast media |
US4584401A (en) * | 1983-10-20 | 1986-04-22 | Biophysica Foundation | Methods and compositions involving polyhydroxylated polyiodo non-ionic contrast media |
US5866100A (en) * | 1995-12-19 | 1999-02-02 | Bracco Research S.A. | Compositions for imaging of the gastrointestinal tract |
WO2000042010A1 (en) * | 1999-01-12 | 2000-07-20 | University Of North Carolina At Chapel Hill | Contrast media for angiography |
US6265610B1 (en) | 1999-01-12 | 2001-07-24 | The University Of North Carolina At Chapel Hill | Contrast media for angiography |
US6498273B2 (en) | 1999-01-12 | 2002-12-24 | The University Of North Carolina | Contrast media for angiography |
US6610850B2 (en) | 1999-01-12 | 2003-08-26 | The University Of North Carolina At Chapel Hill | Contrast media for angiography |
US20040081620A1 (en) * | 1999-01-12 | 2004-04-29 | Gabriel Don A. | Contrast media for angiography |
US6943269B2 (en) | 1999-01-12 | 2005-09-13 | University Of North Carolina - Chapel Hill | Contrast media for angiography |
WO2024093387A1 (en) * | 2022-11-01 | 2024-05-10 | 科睿驰(深圳)医疗科技发展有限公司 | Contrast compound and method for preparing same, and imageable embolization material and method for preparing same |
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